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DNA databases are too white, so genetics doesn’t help everyone. How do we fix this?

It has been two decades since the Human Genome Project first presented a draft of our genetic instruction book. The promise of that medical shot on the moon was that doctors could soon look at an individual’s DNA and prescribe the right medications for that person’s illness or even prevent certain diseases.

That promise, known as precision medicine, has not yet been widely fulfilled. True, researchers are gaining clues about some genetic variants related to certain conditions and some that affect the functioning of drugs in the body. But many of these advances have only benefited one group: people whose ancestral roots come from Europe. In other words, white people.

Instead of a truly human genome that represents everyone, “what we have is essentially a European genome,” says Constance Hilliard, evolution historian at the University of North Texas at Denton. "That data doesn't work for anyone other than people of European descent."

It talks about something more than the reference genome of the Human Genome Project. That database is just one of many that researchers are using to develop precision medicine strategies. Often these genetic databases are based on data primarily from white participants. But race is not the issue. The problem is that, collectively, these data add up to a catalog of genetic variants that do not represent the full range of human genetic diversity.

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When people of African, Asian, Native American, or Pacific Islander descent receive a DNA test to determine if they have inherited a variant that can cause cancer, or if a particular drug will work for them, they are often left with more questions than answers. The results often reveal “variants of uncertain importance,” leaving physicians with little useful information. This happens less often for people of European descent. That disparity could change if genetics included a more diverse group of participants, according to the researchers (SN: 17/09/16, p. 8).

One solution is to make custom reference genomes for populations whose members die of cancer or heart disease at higher rates than other groups, for example, or who face other worse health outcomes, Hilliard suggests.

And the more specific the better. For example, African Americans who were descended from slaves have geographical and ecological backgrounds, as well as evolutionary and social histories different from those of recent African immigrants to the United States. Those stories have left footprints on DNA that can make a difference in people’s health today. The same goes for Indians from various parts of the world and Latinos from Mexico versus the Caribbean or Central or South America.

Researchers have made efforts to increase diversity among participants in genetic studies, but much remains to be done. How to involve more people from diverse backgrounds, going beyond race and ethnicity to include geographical, social and economic diversity, in genetic research is fraught with thorny ethical issues.

To get the audience into the conversation, Science News posed some key questions to readers who watched a short video of Hilliard explaining his views.

Time and time again, respondents to our non-scientific research have said that genetic research is important to improve healthcare. But our respondents, mostly white, had mixed opinions on whether the solution is custom projects as Hilliard proposes or a more widespread effort to add variants to the existing reference human genome. Many people were concerned that pointing out genetic differences could reinforce misconceptions of racial inferiority and superiority and lead to more discrimination.

illustration of a DNA strandDelphine Lee

Why is genetics so white?

Some of our readers have asked how genetic research came to this state in the first place. Why is genetic research so white and what do we do about it?

Let’s start with the project that makes precision medicine a possibility: the Human Genome Project, which produced the human reference genome, a kind of master plan of the genetic composition of humans. The reference genome was initially constructed from the DNA of people who responded to an advertisement in Buffalo News in 1997.

Although many people think that the reference genome is mostly white, it is not, says Valerie Schneider, a staff scientist at the National Library of Medicine in the United States and a member of the Genome Reference Consortium, the group responsible for maintaining the genome. of reference. The database is a musk of more than 60 people of DNA.

An African-American man, nicknamed RP11, contributed 70 percent of the DNA in the reference genome. About half of its DNA was inherited from European ancestors and half from ancestors in sub-Saharan Africa. Another 10 people, including at least one person from East Asia and seven of European descent, together contributed about 23 percent of the DNA. And the DNA of more than 50 people is represented in the remaining 7 percent of the reference, Schneider says. Information on the ethnic and racial backgrounds of most taxpayers is unknown, she said.

All humans have basically the same DNA. Two people are 99.9 percent genetically identical. That’s why a reference genome makes sense. But the 0.1 percent difference between individuals (all spelling variations, typographical errors, insertions, and deletions sprinkled throughout the text of the human instruction book) contributes to differences in health and disease.

Much of what is known about how that 0.1 percent genetic difference affects health comes from a type of research called genome-wide association studies or GWAS. In these studies, scientists compare the DNA of people with a particular disease with the DNA of those who do not have it. The goal is to discover common genetic variants that may explain why one person is susceptible to that disease while another is not.

In 2018, people of European descent accounted for more than 78 percent of participants in GWAS, as reported by researchers at Cell in 2019. That is an improvement from 2009, when 96 percent of participants had European ancestors, as reported by researchers in Nature.

Most research funded by the U.S. advocate for biomedical research, the National Institutes of Health, is conducted by scientists who identify as white, says Sam Oh, an epidemiologist at the University of California, San Francisco. Black and Hispanic researchers collectively receive about 6 percent of grants for research projects, according to NIH data.

“Generally, the participants who are easiest to hire are people who look like scientists themselves, people who share a similar language, a similar culture. It’s easier to establish a relationship and you may already have forays into the communities you’re trying to hire, ”says Oh.

illustration of a DNA strandDelphine Lee

When origins matter

Hilliard's hypothesis is that precision medicine, which adapts treatments based on a person's genetic data, lifestyle, environment, and physiology, is more likely to succeed when researchers consider the histories of groups that have worse health outcomes. For example, black Americans descended from enslaved people have higher rates of kidney disease and high blood pressure and higher mortality rates for certain types of cancer than other ethnic and racial groups in the United States.

In her work as an evolutionary historian studying the people and cultures of West Africa, Hilliard was able to discover one of the reasons why African Americans of slave descent die from certain types of breast and prostate cancer at higher rates than white people. but they have lower rates. osteoporosis, a brittle bone disease. African Americans have a variant of a gene called TRPV6 that helps their cells take in calcium. Overactive TRPV6 is also a hallmark of breast and prostate cancers that disproportionately kill blacks in the United States.

The variant can be traced back to the ancestors of some African Americans: Niger-speaking West Africans-Congo. In that part of West Africa, the tsetse fly kills cattle, making dairy farming unsustainable. Those ancestral people typically consumed between 200 and 400 milligrams of calcium per day. The calcium-absorbing version of TRPV6 has helped the body meet its calcium needs, Hilliard hypothesized. Today, the descendants of some of these people still carry the most absorbent version of the gene, but consume more than 800 milligrams of calcium each day.

Assuming African American women have the same dietary calcium requirement as women of European descent may lead doctors to recommend a higher calcium intake, which may inadvertently encourage the growth of breast and prostate cancers, Hilliard reported in the Journal of Cancer Research & Therapy in 2018.

“No one is connecting the dots,” Hilliard says, because most research has focused on the European version of TRPV6.

illustration of a DNA strandDelphine Lee

One size does not fit all

Some doctors and researchers advocate racialized medicine in which race is used as a proxy for a patient’s genetic makeup and treatments are tailored accordingly. But racialized medicine can counterattack. Take clopidogrel blood thinner, sold under the brand name Plavix. It is received by people at risk of heart attack or stroke. An enzyme called CYP2C19 converts the drug to its active form in the liver.

Some versions of the enzyme do not convert the drug to its active form very well, if they do. “If you have the variant of the enzyme gene that won’t convert (the drug), you’re essentially taking a placebo and you pay 10 times more for something that won’t do what another thing (aspirin) will do,” Oh says.

Inactive versions are more common among Asians and Pacific Islanders than among people of African or European descent. But just saying the drug won’t work for someone who ticked the Pacific Islands box on a medical history form is too simplistic. Between 60 and 70 percent of the people of the insular Melanesian nation of Vanuatu take the inactive forms. But only about 4 percent of fellow Pacific Islanders in Fiji and the Polynesian islands of Samoa, Tonga, and the Cook Islands, and 8 percent of New Zealand Maori have inactive forms.

Assuming someone has a low-yielding enzyme based on their ethnicity is not helpful, according to Nuala Helsby of the University of Auckland in New Zealand. These examples “reiterate the importance of assessing the individual patient rather than relying on inappropriate ethnic-based assumptions for drug dosing decisions,” he wrote in the British Journal of Clinical Pharmacology in 2016.

A much better approach than assuming that ethnicity indicates genetic makeup or that everyone is like Europeans is to analyze a person’s DNA and have an accurate reference genome to compare, Hilliard says. Deciding which genomes to create should be based on known health disparities.

"We have to stop talking about race and we have to stop talking about color blindness." Instead, researchers need to consider the very particular circumstances and environments to which a person’s ancestors have adapted, Hilliard points out.

illustration of a DNA strandDelphine Lee

What is diversity in genetics?

Recruiting people from around the world to participate in genetic research may seem like the way to increase diversity, but that’s a fallacy, Hilliard says. If you really want genetic diversity, look at Africa, she says.

Humans originated in Africa and the continent is home to the most genetically diverse people in the world. Ancestors of Europeans, Asians, Native Americans, and Pacific Islands carry only part of that diversity, so genome sequencing of geographically dispersed people will not capture the full range of variants. But genome sequencing of 3 million people in Africa could accomplish that task, medical geneticist Ambroise Wonkam of the University of Cape Town in South Africa proposed on February 10 in Nature (SN Online: 22/02/21).

Wonkam is a leader in H3Africa or in Human Heritage and Health in Africa. That project cataloged genetic diversity in sub-Saharan Africa by deciphering the genomes of 426 people representing 50 groups on the continent. The team found more than 3 million genetic variants that have never been seen before, researchers reported on Oct. 28 in Nature. "What we've found is that populations that aren't well represented in today's databases are where we get the most; you see a lot more variation there," says Neil Hanchard, a geneticist and doctor at Baylor College of Medicine in Houston.

What’s more, groups living next to each other can be genetically distinct. For example, the Berom of Nigeria, a large ethnic population of approximately 2 million people, has a genetic profile more similar to East African groups than to West African neighboring groups. In many genetic studies, scientists use another large Nigerian group, the Yoruba, "as the target for Africa. But that is probably not representative of Nigeria, let alone Africa," Hanchard says.

This is why Hilliard advocates separate reference genomes or similar tools for groups with health problems that may be related to their genetic and localized geographical ancestry. For West Africa, for example, this may mean different reference data sets for coastal groups and more inland regions, the birthplace of many African American ancestors.

Some countries have begun to build specialized reference genomes. China has compiled a reference of the world's largest ethnic group, the Chinese Han. A recent analysis indicates that the Chinese can be divided into six subgroups from different parts of the country. The China Genome Project also collects data on nine ethnic minorities within its borders. Denmark, Japan, and South Korea are also creating country-specific reference genomes and cataloging genetic variants that can contribute to the health problems facing their populations. It remains to be seen whether this approach will improve health care.

People often have the notion that human groups exist as isolated and discrete populations, says Alice Popejoy, a public health geneticist and computer biologist at Stanford University. “But really as a human species we’ve been moving and mixing for hundreds of thousands of years,” he says. "It gets very complicated when you start talking about different reference genomes for different groups." There are no easy dividing lines. Even if separate reference genomes were constructed, it is not clear how a physician would decide which reference is appropriate for an individual patient.

illustration of a DNA strandDelphine Lee

Concern for discrimination

A major drawback to Hilliard’s proposal may be social rather than scientific, according to some Science News readers.

Many interviewees to our survey expressed concern that even well-meaning scientists could do research that would ultimately increase bias and discrimination toward certain groups. As one reader said, “the idea of ​​diversity extends into a scenario where racial differences will be emphasized and commonalities minimized. This is really the entrance to a racist philosophy. "

Another reader commented: "The fear is that the differences that are found will be exploited by those who want to denigrate others." Another added, "The idea that there are big genetic differences between populations is a can of worms, right?"

In fact, the Chinese government suffered a fire for using DNA to identify members of the Uyghur Muslim ethnic group, targeting them for surveillance and sending some to "re-education camps."

People need a better understanding of what it means when geneticists talk about human diversity, says Charles Rotimi, genetic epidemiologist and director of the Center for Research in Genomics and Global Health at the U.S. National Human Genome Research Institute or NHGRI in Bethesda . Md suggests starting with "our common ancestry, where we all start before going to different environments." Because the human genome is able to adapt to different environments, humans carry signatures from some of the geographic locations where their ancestors settled. “We need to understand how this has influenced our biology and our history,” Rotimi says.

illustration of a DNA strand made of peopleExpanding DNA databases to include a broader mix of people may reveal more relevant variants for some common diseases. Delphine Lee

Researchers can work to understand the genetic diversity within our genome “without invoking old prejudices, without putting our own social constructs on it,” he says. "I don't think the problem is the genome. I think the problem is humanity."

Lawrence Brody, director of NHGRI's Division of Genomics and Society, agrees: "Today's scientists have to possess the discrimination that happened in previous generations, like the Tuskegee experiment, although we are a long way from that." During Tuskegee’s infamous experiment, African American men with syphilis did not receive a treatment that could cure the infection.

“We want the fruits of genetic research to be shared by everyone,” Brody says. It is important to determine when genetic differences contribute to the disease and when they do not. Especially for common diseases, such as heart disease and diabetes, genetics can be secondary to social and economic factors, such as access to health care and fresh food, for example, or excessive stress, racism, and racial prejudice in medicine. be careful. The only way to know what you are playing is to collect the data and this includes making sure that the data is as diverse as possible. “The ethical issue is making sure you do that,” Brody says.

Hilliard says the argument that minorities become more vulnerable when they open up to genetic research is valid. “Genomics, like nuclear fusion, can be armed and dangerous,” she says in response to readers ’concerns. “Minorities can choose to stay out of the genomic revolution or they can make full use of it,” adding their genetic data to the mix.

illustration of a DNA strandDelphine Lee

Different priorities

Some groups choose to stay clear, although scientists are trying to recruit them for genetic studies. The promise that communities that donate their DNA will one day reap the benefits may prove difficult.

“We’re telling these communities that this will reduce health disparities,” says Keolu Fox, a native Hawaiian geneticist and human at the University of California, San Diego. But so far, precision medicine has not produced drugs or brought health benefits to communities of color, he noted last July in the New England Journal of Medicine. "I'm not really seeing the impact on (the Hawaiian natives), the Navajo nation, on the Cheyenne River, Standing Rock. In the black and brown communities, at least, last, the look, we don't see the … impact," he says. Fox.

This is because "in this country we have a real basic infrastructure problem." Millions of people do not have health care. “We have people on reserves who don’t have access to clean water, who don’t have … the internet,” he says. Improving infrastructure and access to health care would do much more to eliminate health disparities than any genetics project could do at the moment, he says.

Many Native American tribes have opted for genetic research. “People ask,‘ How do we make indigenous peoples feel comfortable relating to genomics? "" Says Krystal Tsosie, a member of the Navajo nation (Diné), a geneticist at Vanderbilt University in Nashville and co-founder of the Native Biodata Consortium. "That should never be the issue. It seems coercive and there is always an intention present when you formulate the question that way." Instead, researchers should ask themselves how to protect tribes that choose to research genetically.

And privacy issues become a big issue for small groups, such as the 574 Native American tribal nations recognized in the United States or isolated religious or cultural groups like the Amish or Hutterites. If a member of that group decides to donate DNA to a genetic project, that presentation can paint a genetic portrait of all the members of the group. Such decisions should not be left in individual hands, Tsosie says; it should be a community decision.

Hilliard says the resistance of minorities to participating in genetic research is more than a fear of being singled out; it is the result of being experienced, but seeing medical advances only benefits white people.

“Medical researchers just need to get something that benefits someone who is not European,” he says. "If blacks or Native Americans or other underrepresented groups saw even a single example that someone of their ethnicity was cured of the many chronic (common) diseases and specific cancers for those at high risk, that paranoia would evaporate overnight." .

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